| First Author | Yamamoto S | Year | 2011 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 31 |
| Issue | 12 | Pages | 2856-64 |
| PubMed ID | 21979434 | Mgi Jnum | J:191451 |
| Mgi Id | MGI:5461775 | Doi | 10.1161/ATVBAHA.111.237198 |
| Citation | Yamamoto S, et al. (2011) Macrophage polarization by angiotensin II-type 1 receptor aggravates renal injury-acceleration of atherosclerosis. Arterioscler Thromb Vasc Biol 31(12):2856-64 |
| abstractText | OBJECTIVE: Angiotensin II is a major determinant of atherosclerosis. Although macrophages are the most abundant cells in atherosclerotic plaques and express angiotensin II type 1 receptor (AT1), the pathophysiologic role of macrophage AT1 in atherogenesis remains uncertain. We examined the contribution of macrophage AT1 to accelerated atherosclerosis in an angiotensin II-responsive setting induced by uninephrectomy (UNx). METHODS AND RESULTS: AT1(-/-) or AT1(+/+) marrow from apolipoprotein E deficient (apoE(-/-)) mice was transplanted into recipient apoE(-/-) mice with subsequent UNx or sham operation: apoE(-/-)/AT1(+/+)-->apoE(-/-)+sham; apoE(-/-)/AT1(+/+) -->apoE(-/-)+UNx; apoE(-/-)/AT1(-/-)-->apoE(-/-)+sham; apoE(-/-)/AT1(-/-)-->apoE(-/-)+UNx. No differences in body weight, blood pressure, lipid profile, and serum creatinine were observed between the 2 UNx groups. ApoE(-/-)/AT1(+/+) -->apoE(-/-)+UNx had significantly more atherosclerosis (16907+/-21473 versus 116071+/-8180 mum(2), P<0.05). By contrast, loss of macrophage AT1 which reduced local AT1 expression, prevented any effect of UNx on atherosclerosis (77174+/-9947 versus 75714+/-11333 mum(2), P=NS). Although UNx did not affect total macrophage content in the atheroma, lesions in apoE(-/-)/AT1(-/-)-->apoE(-/-)+UNx had fewer classically activated macrophage phenotype (M1) and more alternatively activated phenotype (M2). Further, UNx did not affect plaque necrosis or apoptosis in apoE(-/-)/AT1(-/-)-->apoE(-/-) whereas it significantly increased both (by 2- and 6-fold, respectively) in apoE(-/-)/AT1(+/+) -->apoE(-/-) mice. Instead, apoE(-/-)/AT1(-/-)-->apoE(-/-) had 5-fold-increase in macrophage-associated apoptotic bodies, indicating enhanced efferocytosis. In vitro studies confirmed blunted susceptibility to apoptosis, especially in M2 macrophages, and a more efficient phagocytic function of AT1(-/-) macrophages versus AT1(+/+). CONCLUSIONS: AT1 receptor of bone marrow-derived macrophages worsens the extent and complexity of renal injury-induced atherosclerosis by shifting the macrophage phenotype to more M1 and less M2 through mechanisms that include increased apoptosis and impaired efferocytosis. |
